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TETRANITROMETHANE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tetranitromethane is a nitrated methane derivative used as an oxidizer in rocket propellants, as an explosive, to increase the cetane number of diesel fuels, and as a laboratory reagent (ACGIH, 1983; Budavari, 1996; Lewis, 1993).

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C-N4-O8

Available Forms Sources

    A) FORMS
    1) DESCRIPTION:
    1) Pale yellow liquid (Budavari, 1996; Hathaway et al, 1991a)
    2) Colorless liquid with a pungent odor (Lewis, 1993)
    3) Colorless, oily fluid (Clayton & Clayton, 1993)
    B) SOURCES
    1) Tetranitromethane occurs as a contaminant of crud trinitrotoluene (TNT) and is thought to be primarily responsible for TNT's irritant properties (Clayton & Clayton, 1993).
    C) USES
    1) Oxidizer or more propellent in rocket fuel; as explosive in admixture with toluene; to increase cetane number of diesel fuels; reagent for detecting the presence of double bonds in organic compounds and to nitrate tyrosine residues in proteins and peptides (Budavari, 1996; Lewis, 1993). It has been proposed for use as an irritant war gas (Budavari, 1996; Lewis, 1993).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Human fatalities have occurred from tetranitromethane exposure. It is a potent irritant of the eyes and mucous membranes. Inhalation may produce respiratory tract irritation, dyspnea, bronchopneumonia, or pulmonary edema. Headache and weakness occur with chronic vapor exposure.
    1) Experimental animals have developed central nervous system damage, anemia, and fatty degeneration of the liver and kidneys from exposure. Direct skin contact may cause mild burns.
    2) Tetranitromethane occurs as an impurity in crude TNT, and is thought to be mainly responsible for that material's irritant properties.
    0.2.4) HEENT
    A) Eye, nose and throat irritation may occur.
    0.2.6) RESPIRATORY
    A) Respiratory tract irritation, dyspnea, or bronchopneumonia may be seen. Noncardiogenic pulmonary edema may occur.
    0.2.8) GASTROINTESTINAL
    A) Based on this agent's other irritant properties, esophageal or gastrointestinal tract irritation or burns might develop following ingestion.
    0.2.9) HEPATIC
    A) In experimental animals, fatty degeneration of the liver has been reported. There are no reports of human hepatotoxicity from tetranitromethane exposure.
    0.2.10) GENITOURINARY
    A) In experimental animals, fatty degeneration of the kidneys has been reported. There are no reports of human nephrotoxicity from tetranitromethane exposure.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia has occurred with significant exposure.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of tetranitromethane in humans.
    0.2.22) OTHER
    A) Human fatalities have occurred.

Laboratory Monitoring

    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    C) Cyanotic patients should have methemoglobin levels measured.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Because of potential irritant effects, DO NOT induce EMESIS.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) Obtain baseline hemoglobin, hematocrit, and liver and renal function tests. If cyanosis is present, methemoglobin levels should be measured and followed.
    E) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    F) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    G) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    H) Supportive care should be given if liver or renal failure occur.
    I) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
    0.4.3) INHALATION EXPOSURE
    A) Baseline laboratory tests and chest x-ray should be obtained in patients with significant exposure. Patients with significant methemoglobinemia may require intravenous methylene blue. Supportive care should be given if liver or renal failure occurs.
    B) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    C) OXYGEN: Provide supplemental humidified oxygen and obtain baseline arterial blood gases and chest x-ray. Pulmonary edema may occur and have a delayed onset.
    D) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    E) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    F) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    G) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    H) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) The lowest lethal human dose (LDLo) by inhalation exposure is about 500 mg/kg. Eye and upper respiratory tract irritation occur at airborne concentrations greater than 1 ppm.

Clinical Effects

Summary Of Exposure

    A) Human fatalities have occurred from tetranitromethane exposure. It is a potent irritant of the eyes and mucous membranes. Inhalation may produce respiratory tract irritation, dyspnea, bronchopneumonia, or pulmonary edema. Headache and weakness occur with chronic vapor exposure.
    1) Experimental animals have developed central nervous system damage, anemia, and fatty degeneration of the liver and kidneys from exposure. Direct skin contact may cause mild burns.
    2) Tetranitromethane occurs as an impurity in crude TNT, and is thought to be mainly responsible for that material's irritant properties.

Heent

    3.4.1) SUMMARY
    A) Eye, nose and throat irritation may occur.
    3.4.3) EYES
    A) CONJUNCTIVITIS - Eye irritation has been noted in workers exposed to vapor (Hathaway et al, 1978).
    3.4.5) NOSE
    A) MUCOSAL IRRITATION - Workers exposed to tetranitromethane vapor have experienced irritation of the nasal mucosa and rhinorrhea (Clayton & Clayton, 1993; Hathaway et al, 1991).
    3.4.6) THROAT
    A) MUCOSAL IRRITATION - Exposure to vapor causes irritation of the throat (Clayton & Clayton, 1993).

Respiratory

    3.6.1) SUMMARY
    A) Respiratory tract irritation, dyspnea, or bronchopneumonia may be seen. Noncardiogenic pulmonary edema may occur.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Exposure to vapor can produce irritation of the respiratory mucosa, dyspnea, and bronchopneumonia (ACGIH, 1992; (Hathaway et al, 1991).
    B) ACUTE LUNG INJURY
    1) Experimental animals have developed noncardiogenic pulmonary edema following inhalation exposure to tetranitromethane (Clayton & Clayton, 1993) ACGIH, 1992; (Hathaway et al, 1991).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) Intravenous injection of tetranitromethane in experimental animals produced unspecified central nervous system damage (Hathaway et al, 1991). There are no reports of human CNS damage from tetranitromethane exposure.

Gastrointestinal

    3.8.1) SUMMARY
    A) Based on this agent's other irritant properties, esophageal or gastrointestinal tract irritation or burns might develop following ingestion.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) Based on this agent's other irritant properties, esophageal or gastrointestinal tract irritation or burns might develop following ingestion.

Hepatic

    3.9.1) SUMMARY
    A) In experimental animals, fatty degeneration of the liver has been reported. There are no reports of human hepatotoxicity from tetranitromethane exposure.
    3.9.2) CLINICAL EFFECTS
    A) STEATOSIS OF LIVER
    1) Fatty degeneration of the liver has been reported in experimental animals following inhalation exposure (ACGIH, 1992). There are no reports of human hepatotoxicity from tetranitromethane exposure.

Genitourinary

    3.10.1) SUMMARY
    A) In experimental animals, fatty degeneration of the kidneys has been reported. There are no reports of human nephrotoxicity from tetranitromethane exposure.
    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) Fatty degeneration of the kidneys has been reported in experimental animals following inhalation exposure (ACGIH, 1992). There are no reports of human nephrotoxicity from tetranitromethane exposure.

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia has occurred with significant exposure.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia has been described (Hathaway et al, 1991).
    B) ANEMIA
    1) Intravenous injection in experimental animals has caused anemia (Hathaway et al, 1991). This effect has not been reported in exposed humans.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) There are conflicting reports of whether or not skin irritation occurs from contact with tetranitromethane. Clayton & Clayton (1993) state that repeated contact does not produce skin irritation in experimental animals or humans, while Hathaway et al (1991) note that direct dermal contact may cause mild burns.

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no human data were available to assess the teratogenic potential of tetranitromethane.
    3.20.3) EFFECTS IN PREGNANCY
    A) METHEMOGLOBINEMIA
    1) Agents which can induce methemoglobinemia are of theoretical concern for potential harm to the fetus. Fetal hemoglobin is more readily oxidized to methemoglobin than the adult form, it is less rapidly converted back to normal hemoglobin, and the developing organ systems, especially the nervous system, are more sensitive to lack of oxygen than in adults. Refer to nitrobenzene document for more information.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS509-14-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Tetranitromethane
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of tetranitromethane in humans.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Tetranitromethane is listed in the NTP Seventh Annual Report on Carcinogens (HSDB , 1996).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Tetranitromethane is an experimental animal carcinogen. Inhalation of the vapor produced lung tumors (adenocarcinomas, squamous cell carcinomas, or adenosquamous carcinomas) in mice exposed to 0.5 to 2 ppm and in rats exposed to 2 or 5 ppm for 6 hours/day, 5 days/week for 2 years (NTP, 1990; Bucher et al, 1991).
    2) The combination of low concentrations sufficient to induce lung tumors, and the nearly 100% response of animals, was unprecedented in the history of the National Toxicology Program at the time these studies were done (Bucher et al, 1991).

Genotoxicity

    A) Tetranitromethane has been genotoxic in several short-term test systems.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    C) Cyanotic patients should have methemoglobin levels measured.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    B) HEMATOLOGIC
    1) If cyanosis is present, methemoglobin levels should be measured and followed.
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    2) MONITORING
    a) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If respiratory tract irritation is present, monitor chest x-ray.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Patients with significant inhalation exposure or respiratory irritation may develop delayed pulmonary edema and should be observed in a controlled setting.

Monitoring

    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    C) Cyanotic patients should have methemoglobin levels measured.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT-RECOMMENDED
    1) Because of potential irritant effects, DO NOT induce EMESIS.
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL/CATHARTIC
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Supportive measures should be taken if hepatic or renal failure occur.
    B) MONITORING OF PATIENT
    1) Obtain baseline hemoglobin, hematocrit, and liver and renal function tests. If cyanosis is present, methemoglobin levels should be measured and followed.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    D) IRRITATION SYMPTOM
    1) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) OXYGEN
    1) Provide supplemental humidified oxygen and obtain baseline arterial blood gases and chest x-ray. Pulmonary edema may occur and have a delayed onset.
    B) BRONCHOSPASM
    1) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    C) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) The lowest lethal human dose (LDLo) by inhalation exposure is about 500 mg/kg. Eye and upper respiratory tract irritation occur at airborne concentrations greater than 1 ppm.

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) Airborne concentrations as low as 0.1 ppm have been fatal in experimental animals (RTECS , 1996).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated exposure is not well established.
    2) Exposed laboratory workers developed lacrimation and upper respiratory tract irritation when airborne concentrations exceeded 1 ppm (Hathaway et al, 1991).
    3) Airborne concentrations in excess of 1 ppm cause lacrimation and upper respiratory irritation, whereas 0.4 ppm may cause mild irritation (Hathaway et al, 1991).

Workplace Standards

    A) ACGIH TLV Values for CAS509-14-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Tetranitromethane
    a) TLV:
    1) TLV-TWA: 0.005 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Not Listed
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    c) TLV Basis - Critical Effect(s): Eye and URT irr; URT cancer
    d) Molecular Weight: 196.04
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS509-14-8 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Tetranitromethane
    2) REL:
    a) TWA: 1 ppm (8 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 4 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS509-14-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Tetranitromethane
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Tetranitromethane
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Tetranitromethane
    5) MAK (DFG, 2002): Category 2 ; Listed as: Tetranitromethane
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Tetranitromethane
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS509-14-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Tetranitromethane
    2) Table Z-1 for Tetranitromethane:
    a) 8-hour TWA:
    1) ppm: 1
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 8
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: HSDB, 1996 ITI, 1988; RTECS, 1996
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 53 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 375 mg/kg
    3) LD50- (ORAL)RAT:
    a) 130 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Tetranitromethane is a direct irritant of eyes, mucous membranes, and perhaps skin (Hathaway et al, 1991).
    B) Combustion of tetranitromethane produces nitrogen oxides which are also potent respiratory tract irritants.
    C) The acute toxicity of tetranitromethane probably involves at least two mechanisms: inactivation of enzymes, peptides, and proteins through nitration of essential tyrosyl and sulfhydryl residues, and oxidation of the iron in heme to form methemoglobin. Its irritant effects may be related to its properties as an acid.
    D) Methemoglobinemia was induced in animals exposed by the oral but not by the inhalation or IV routes; this result implies a role of nitroreductase in the gut for the production of methemoglobin (ACGIH, 1991).

Physicochemical

Physical Characteristics

    A) Tetranitromethane has a characteristic acrid, biting odor (Clayton & Clayton, 1993).
    B) Pale yellow or colorless, oily liquid, with a pungent odor (Budavari, 1996) Hathaway, 1991; (Lewis, 1993; Clayton & Clayton, 1993)

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 196.04 (Budavari, 1996)

References

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